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SOKE  PROBLEMS  OF  INTERMEDIARY  METABOLISM 


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SOME  PROBLEMS  OF  INTERMEDIARY 
METABOLISM. 


CO!  IJWW'A    UNIVCPP.TV 

DEPARTMENT  OF  PHYSIOLOGY 

College  of  Physicians  and  8-  ^qecmc 
4st  west  fifty-ninth  strect 

NEW  YORK 


THE   SHATTUCK   LECTURE. 


SOME  PROBLEMS  OF  INTERMEDIARY 
METABOLISM. 


Bi    RUSSELL  II.  CHITTENDEN,  Ph.D. 

OF  HEW    MAVKN,   CONN. 


Delivered  at  the  Annual  Meeting  •>('  the  Massachusetts  Medical  Society, 

June   13,   100.J. 


DEPARTMENT  OF  PHYSIOLOGY 

COUJttE  OF  PHYSICIANS  *"°  *"G*»8 
487  WEST  FIFTY-NINTH  STRfcC 


NEW  YORK 

SOME    PROBLEMS    OF    INTERMEDIARY 
METABOLISM. 


It  requires  little  imagination  and  little  knowledge  of 
physiology  to  comprehend  that  upon  a  true  understanding 
and  rightful  interpretation  of  the  many  and  varied  me- 
tabolic phenomena  of  the  body  depends  in  large  measure 
the  accuracy  of  our  knowledge  of  the  processes  of  life,  both 
in  health  and  in  disease.  Vet  as  Sir  Michael  Foster  has 
clearly  pointed  out,  it  is  wholly  impossible  at  present  to 
make  any  connected  or  continuous  story  of  the  metabolic 
changes  undergone  by  the  individual  constituents  of  the 
food,  the  body  or  the  waste  products.  In  the  chain  of 
events  from  the  assimilation  of  the  digested  food  materials 
by  the  hungry  tissues  down  to  the  elimination  of  the  final 
waste  products  by  the  kidneys,  lungs  and  skin,  are  many 
broken  and  missing  links  by  which  the  continuity  of  the 
Btory  is  destroyed  and  we  are  compelled  to  fill  the  gaps  by 
guesses  and  conjectures,  too  often  widely  divergent  from 
the  truth. 

The  very  existence  of  these  gaps  and  breaks  in  our 
knowledge,  however,  serves  as  an  ever-present  stimulus  in- 
citing renewed  activity  iii  the  search  for  truth  and  enlight- 
enment. As  is  often  the  case,  this  Bearch  brings  added 
complexity  l>v  opening  up  vistas  that  were  not  supposed  to 
exist,  and  our  thoughts  and  our  experiments  take  a  new 
turn,  from  time  to  time,  as  additional  tacts  are  brought  to 
the  Burface,  with  n  suggestion  of  new  methods  of  interpre- 
tation.    Advances  are  constantly  being  made;  old  views 


4  SOME    PROBLEMS    OF 

are  undergoing  modifications  or  are  entirely  supplanted  by 
new  theories,  the  result  of  steady  progress  in  knowledge. 
The  gaps  and  breaks  in  the  chain  of  events  that  represents 
the  processes  of  life  are  being  slowly  filled  in,  but  new 
gaps  make  their  appearance,  demanding  additional  knowl- 
edge before  we  can  hope  for  a  perfect  understanding  of  the 
many  and  varied  steps  in  the  metabolic  transformations 
characteristic  of  living  tissues. 

As  has  been  so  clearly  expressed  by  many  writers,  we 
need  full  knowledge  of  all  the  steps  in  the  building  up  and 
breaking  down  of  the  tissue  materials,  with  full  conscious- 
ness of  the  fact  that  a  large  majority  of  the  diseases  of  the 
body  are  the  result  of  a  perversion  of  metabolism .  Further, 
we  realize  full  well  that  it  is  equally  important  to  possess 
knowledge  of  where  these  individual  steps  in  metabolism 
are  located,  if  we  are  to  have  full  comprehension  of  the 
true  functional  activity  of  the  individual  organs  and  tissues 
of  the  body.  We  need  to  know  the  exact  nature  of  each 
link  in  the  chain  of  events,  and  where  each  link  lies  with 
reference  to  the  other  links  of  the  chain.  The  many  de- 
generative changes  that  check  the  activities  of  man  at  a 
time  when  he  should  be  in  the  full  vigor  of  life,  we  fre- 
quently say  are  due  to  the  disorders  of  metabolism  or  nutri- 
tion, recognizing  perhaps  full  well  the  general  character  of 
the  perversion,  but  with  no  adequate  conception  of  exactly 
what  has  occurred  or  what  should  be  done  to  remedy  or 
prevent.  We  lack  knowledge  of  the  intermediary  steps  in 
metabolism,  in  health  and  in  disease,  and  if  we  are  to  in- 
terpret aright  the  conditions  that  bring  about  disease,  to 
say  nothing  of  prevention  and  cure,  we  must  acquire  full 
understanding  of  the  processes  of  intermediary  metabolism, 
their  relationship  to  each  other,  their  general  and  specific 
character  and  the  influences  that  control  their  harmonious 
working. 

As  has  just  been  stated,  many  of  the  gaps  and  breaks  in 


INTERMEDIARY    METABOLISM.  5 

our  knowledge  of  metabolism  have  been  filled  up,  new 
tacts  have  been  brought  to  light,  new  suggestions  have 
been  made,  and  our  knowledge  has  been  correspondingly 
increased.  It  has  therefore  seemed  to  me  that  I  could  not 
I  tetter  fulfil  the  purpose  of  the  Shattuck  lecture  than  to 
present  to  you  some  of  these  problems  of  intermediary 
metabolism  which  of  late  have  been  under  consideration 
and  for  which  we  have  now  a  partial  or  complete  solution. 
Every  active  tissue  of  the  body,  every  glandular  organ, 
every  individual  living  cell,  is  the  seat  of  incessant  chemi- 
cal activity  :  construction  and  destruction  are  going  on  side 
by  side,  new  food  materials  —  proteids,  fats  and  carbohy- 
drates, togethe'r  with  inorganic  salts,  water  and  oxygen  — 
are  continually  being  supplied,  and  passing  into  the  cells 
of  the  various  tissues  or  organs  are  eventually  built  up 
into  the  tissue  material,  or  are  made  more  or  less  completely 
adherent.  Simultaneously,  the  cell  substance  or  the  adhe- 
rent materials  are  undergoing  characteristic  changes.  Se- 
creting  gland  cells  are  manufacturing  enzyme  antecedents 
and  storing  them  up  in  the  cells  for  future  use,  or  are  per- 
haps pouring  the  products  forth  in  slightly  altered  form  to 
give  character  to  the  glandular  secretion.  Other  gland 
cells  are  elaborating  specific  products,  such  as  bile  acids, 
glycogen,  amido-acids  of  various  kinds,  internal  secretions 
to  be  re-absorbed  by  the  blood  and  serve  some  purpose 
elsewhere  in  the  body;  decompositions  of  great  variety  are 
being  carried  on,  and  complex  substances  are  being  broken 

down  into  simpler  with  liberation  of  energy,  manifest  in  the 

form  ot  heat  or    mechanical   work.       And    so  we    have   from 

every  group  of  individualized  cells  in  the  body  a  more  or 
less  continuous  stream  of  katabolic  products,  representa- 
tives of  the  destructive  Changes  taking  place  in    the  cells    of 

the  individual  tissues  or  organs,  further  complexity  is 
introduced  by  the  facl  thai  a  given  set  of  cells  may  show 

many    different    lilies    of  activity.       Thus,   the    hepatic    cells 


G  SOME    PROBLEMS    OF 

not  only  manufacture  bile  acids  and  bile  pigments,  but 
they  likewise  produce  glycogen  from  sugar  and  transform 
sugar  into  glycogen,  they  form  urea  from  various  amido- 
acids  and  ammonia,  they  bring  about  the  construction  and 
destruction  of  uric  acid,  they  decompose  the  hemoglobin 
of  the  blood  and  withdraw  the  iron  from  the  hsematin  mole- 
cule to  manufacture  bilirubin,  they  bring  about  combina- 
tions between  sulphuric  acid  and  certain  aromatic  substances 
such  as  phenol;  in  a  word,  they  are  active  in  carrying  for- 
ward a  great  variety  of  divergent  processes  in  which  oxi- 
dation, hydration  and  dehydration  are  equally  conspicuous. 

These  processes  of  metabolism  may  be  viewed  from  the 
standpoint  of  ultimate  changes,  without  regard  to  the  few 
or  many  intermediary  steps  in  the  process.  Thus,  the 
physiologist  may  study,  for  example,  the  extent  to  which 
the  formation  of  urea  goes  on  in  the  body  under  different 
conditions  of  diet,  etc.,  and  he  may  acquire  much  useful 
information  regarding  the  rate  of  proteid  katabolism,  with- 
out, however,  learning  much  or  anything  of  the  various  in- 
termediary steps  in  the  process  by  which  the  urea  is  elabo- 
rated from  the  proteid  of  the  food  or  of  the  tissues.  It  is 
obvious  that  we  can  acquire  full  and  exact  knowledge  of 
the  way  in  which  urea  is  formed  only  by  searching  out  the 
successive  changes  that  take  place  from  the  primary  break- 
ing down  of  the  proteid  to  the  ultimate  formation  of  urea  ; 
i.  e.,  by  studying  the  intermediary  processes  of  proteid 
katabolism. 

In  any  consideration  of  intermediary  metabolism,  where 
of  necessity  the  action  of  specialized  groups  of  cells — as  in 
individual  tissues  and  organs — is  involved,  we  are  at  once 
confronted  with  the  general  question  as  to  how  the  pro- 
cesses of  destructive  decomposition  are  accomplished.  In 
what  manner  and  by  what  agencies  are  the  processes  of 
katabolism  carried  out?  Until  recent  times  we  have  had 
no  logical  answer  to  this  question.     Physiologists  and  biolo- 


INTERMEDIARY    METABOLISM.  i 

Li'i-rs!  long  held  that  the  processes  going  on  in  living  tissue- 
were  of  far  too  complicated  a  nature  to  admit  of  explanation 
by  chemical  or  physical  means.  Sehonbein,  for  example, 
maintained  that  the  exact  sciences  were  not  sufficiently  de- 
veloped, to  render  possible  any  exact  analysis  of  the  changes 
taking  place  in  living  cells.  It  was  the  fashion  to  assume 
that  it  was  the  functional  activity  of  the  living  cell  as  a 
whole  that  made  possible  the  chemical  changes  characteris- 
tic of  the  tissue  or  gland.  Cell  activity  was  considered  as 
the  result  of  an  inherent  quality  of  the  living  protoplasm, 
and  no  one  agent  or  definite  substance  could  be  held  respon- 
sible for  this  activity.  The  theories  of  vitalism  held  the 
physiologist  in '  a  strong  grasp.  Even  when  ferments  or 
enz vines  gained  gradual  recognition,  their  action  was  con- 
sidered as  purely  extra-cellular,  and  they  were  not  looked 
upon  as  playing  any  special  part  in  metabolism.  In  diges- 
tion, of  course,  their  action  was  manifest,  but  it  was  wholly 
extra-cellular,  though  their  origin  was  intra-cellular. 

Living  cells  produced  enzymes  for  certain  purposes,  but 
there  was  no  evidence  that  the  ordinary  processes  of  kata- 
bolism  with  which  the  cells  might  be  involved  were  con- 
nected in  any  way  with  ferment  or  enzyme  action.  Until 
very  recent  times,  the  yeast  cell  was  taken  as  a  typical  ex- 
ample of  the  then  point  of  view.  It  produced  an  inverting 
ferment  which  could  be  extracted  from  the  cell  and  which 
was  verv  efficient  in  inverting  cane  sugar,  but  the  peculiar 
property  of  the  yeast  cell,  i.  e.,  the  formation  of  carbon 
dioxide  and  alcohol,  was  the  result  of  the  activity  of  the 
cell  as  a  whole.  It  was  considered  as  due  to  an  inherent 
quality  of  the  living  protoplasm.  This  view  prevailed  until 
a  few  yean  ago,  when  Hans  Buchner  showed  that  it  was 
quite   possible  to   press  out  of  the  yeast  cell  a  clear  fluid 

which,  freed    from    all    cellular    elements,   would   still    cause 

alcoholic  fermentation.     Still  later,  an  enzyme  was  isolated 

— zymase — which     breaks    down     sugar     into     alcohol    and 


O  SOME    PROBLEMS    OF 

carbon  dioxide  quite  as  effectively  as  the  yeast  cell  itself. 
In  other  words,  Ave  have  learned  that  this  so-called  vital 
property  of  the  yeast  cell  is  due  entirely  to  an  intra-cellular 
ferment  or  enzyme  which  the  cell  manufactures. 

In  the  animal  body  the  processes  of  metabolism,  as 
judged  from  the  number  and  variety  of  products  formed, 
are  many  and  varied.  It  has  been  customary  to  classify 
these  chemical  processes  under  the  heads  of  hydrolytic 
cleavage,  oxidation,  reduction,  synthesis,  etc.,  and  to-day 
we  are  in  a  position  to  affirm  that  intra-cellular  ferments 
are  the  responsible  agents  in  bringing  about  these  varied 
processes  of  metabolism  in  the  individual  organs  and  tissues 
of  the  body.  There  is  practically  no  process  of  metabolism 
so  intricate  or  obscure  that  it  cannot  well  be  explained  by 
the  action  and  interaction  of  intra-cellular  ferments.  New 
ferments  are  constantly  being  discovered,  new  chemical 
reactions  are  being  traced  to  the  power  of  special  ferments, 
and  we  now  speak  with  great  detail  of  the  various  autolytic 
changes  that  different  glands  and  organs  undergo,  when 
simply  warmed  at  40°C  under  antiseptic  precautions,  be- 
cause of  the  action  of  intra-cellular  ferments  which  are 
practically  present  in  all  tissues. 

Proteolytic  ferments  of  the  trypsin,  or  of  the  newly  dis- 
covered erepsin,  type  are  present  in  most,  if  not  all,  of  the 
tissues  of  the  body.  Muscle,  liver,  kidneys,  lymph  glands, 
lungs,  spleen,  etc.,  all  contain  proteid-dissolving  ferments, 
and  when  the  tissues  are  subjected  to  auto-digestion  or 
autolysis,  such  products  as  the  amido-acids,  leucin  and 
tyrosin,  tryptophan,  glycocoll,  hexone  bases  or  diamino- 
acids,  and  ammonia  result  from  the  breaking  down  of  the 
various  proteids  of  the  tissue.  In  this  connection  it  is  to  be 
noted  that  the  respective  proteids  of  the  individual  tissues 
are  much  more  quickly  affected  by  these  ferments  than  are 
foreign  proteids,  thus  suggesting  that  these  intra-cellular 
enzymes  are  somewhat  different  in  nature  from  the  ordinary 


INTERMEDIARY    METABOLISM.  V 

proteolytic  enzymes  of  the  digestive  juices.  Further,  there 
are  peculiar  ferments  that  act  specifically  upon  the  intra- 
cellular nucleoproteids,  splitting  off  the  nucleic  acid  com- 
plex from  the  proteid  part  of  the  molecule,  and  still  other 
ferments  that  bring  about  a  cleavage  of  the  nucleic  acid 
with  liberation  of  the  contained  purin  bases.  Lastly,  it 
may  be  said  that  the  general  trend  of  action  with  these 
intra-cellular  proteolytic  ferments  is  hydrolytic  cleavage, 
much  the  same  as  the  influence  exerted  by  mineral  acids  or 
by  ordinary  digestive  enzymes. 

Other  types  of  intra-cellular  ferments  exercising  hydro- 
lytic action  accompanied  by  cleavage  are  to  be  found  in 
lipases,  true  adipolytic  ferments  which  split  neutral  fats 
into  glycerin  and  fatty  acids  in  a  fashion  quite  analogous 
to  the  action  of  ordinary  steapsin.  These  lipases  are  found 
in  the  liver  and  other  organs.  Further,  the  kidneys  and 
liver  contain  a  ferment  capable  of  splitting  hippuric  acid 
into  benzoic  acid  and  glycocoll  (8chmiedeberg).  Again, 
Jacoby  has  shown  that  the  liver  will  yield  an  extract  capa- 
ble of  splitting  off  amonia  from  urea,  and  that  the  same 
gland  contains  a  ferment  capable  of  transforming  amido- 
acids  into  amides.  Moreover,  the  liver  and  indeed  the 
kidney-  as  well  have  the  power  of  splitting  up  amides  ; 
a  fact  of  the  utmost  importance  in  intermediary  metabolism. 
Lastly,  glycolytic  action,  in  which  both  cleavage  and  oxi- 
dation >>[  sugars  may  be  involved,  is  likewise  a  function  of 
many  cells;  and  adds  another  striking  illustration  of  intra- 
cellular ferment  action,  by  which  carbohydrate  metabolism 
may  be  carried  forward  in  the  different  tissues  and  organs 
of  the  body. 

<  Oxidation  is  preeminently  one  of  Nature's  ways  of  bring* 

inn  about  alteration  and  decomposition,  and  in  interme- 
diary metabolism  especially,  oxidative  processes  must  be 
quite  conspicuous.  Vet  to-day  we  have  accumulated  a  mass 
of  evidence  tending  to  -how  that  oxidation  in  the  tissues  is 


10  SOME    PROBLEMS    OF 

due  primarily  to  the  presence  and  action  of  a  row  of  more 
or  less  closely  related  though  chemically  distinct  ferments, 
known  collectively  as  oxidases.  Physiological  oxidation 
therefore,  as  it  occurs  in  metabolism,  is  likewise  a  result  of 
intra-cellular  ferment  action.  To  be  sure,  the  blood  is  the 
carrier  to  the  tissue  cells  of  the  necessary  oxygen,  but  the 
process  of  oxidation,  with  such  chemical  reactions  as  is  in- 
volved, is  due  to  the  action  of  the  intra-cellular  oxidases. 
It  is  well  to  recall  that  Schonbein  originally  drew  attention 
to  the  fact  that  the  blood,  and  tissues  as  well,  had  the 
power  when  fresh  of  splitting  off  oxygen  from  hydrogen 
peroxide,  but  lost  the  power  when  heated  to  90-100°. 
This  phenomenon,  however,  is  not,  as  was  at  one  time 
thought,  simply  a  general  ferment  indicator,  but  is  due  to 
the  action  of  specific  oxidases,  some  of  which  can  actually 
be  precipitated  from  the  fluids  containing  them,  and  more- 
over differ  among  themselves  as  to  the  degree  in  which 
they  are  distributed  among  the  different  tissues  and  organs 
of  the  body.  The  spleen,  liver,  pancreas,  thymus,  muscle, 
brain  and  ovaries  are  noticeably  rich  in  oxidizing  ferment. 
In  fact,  the  physiologist  to-day  has  knowledge  of  a  large 
number  of  intra-cellular  oxidases,  more  or  less  distinct 
from  each  other,  to  some  of  which  distinct  names  have 
been  given  indicative  of  their  special  lines  of  activity,  viz., 
aldehydase,  a  ferment  which  oxidizes  aldehydes  to  their 
corresponding  acids,  and  present  in  the  liver,  kidneys, 
testicles,  suprarenale,  brain,  lungs,  thymus  and  salivary 
glands  ;  tyrosinase,  a  ferment  which  oxidizes  benzol  deriva- 
tives, especially  tyrosin  ;  and  indolphenol-oxidase,  a  cor- 
responding ferment  present  in  the  pancreas,  thymus,  spleen, 
and  salivary  glands,  but  absent  from  the  muscle  and  kid- 
neys. 

As  can  easily  be  imagined,  these  facts  throw  new  light 
upon  the  methods  of  intermediary  metabolism.  They  show 
us  that  the  individual  gland   and   tissue  cells  are  provided 


INTERMEDIARY    METABOLISM.  11 

with  efficient  agents  for  accomplishing  chemical  changes  of 
great  variety.  We  are  no  longer  forced  to  think  or  speak 
in  vague  terms  of  the  somewhat  mystical  changes  that  go 
on  in  living  tissues,  hut  we  have  acquired  sufficient  knowl- 
edge to  understand  that  the  individual  cells  of  the  body  are 
provided  with  intra-cellular  ferments  of  definite  character 
by  which  the  metabolic  changes  are  produced.  These 
newly  discovered  enzymes  are  of  such  widely  divergent 
nature  and  so  broadly  distributed  among  the  tissues  of  the 
body  that  they  offer  an  adequate  explanation  of  the  many 
chemical  changes  that  occur  in  ordinary  metabolic  processes. 
Further,  when  it  is  remembered  that  practically  all  tissue 
cells  contain  proteolytic  enzymes  capable  of  transforming 
their  own  proteids  into  simpler  products,  and  that  in  addi- 
tion they  have  special  enzymes  endowed  with  a  variety  of 
powers,  we  see  opening  before  us  simple  chemical  methods 
of  tracing  out  the  individual  steps  in  the  gradual  breaking 
down  of  the  complex  molecules  of  tissue  material  into  the 
relatively  simple  bodies  which  we  classify  as  intermediate 
and  end  products  of  tissue  metabolism. 

Let  us  now  consider  more  in  detail,  and  from  the  stand- 
point of  what  has  already  been  said,  some  specific  examples 
of  intermediary  metabolism.  By  the  older  methods  of  in- 
vestigation, the  physiologist  was  compelled  to  rely  mainlv 
for  information  upon  such  data  as  could  be  obtained  by 
careful  study  of  the  urine,  reinforced  by  examination  of  the 
individual  glands  and  tissues.  The  detection  in  the  latter 
<»f  specific  products  led  to  the  inference  that  these  substances 
were    formed    ill    the   glands    under  examination,  but  it  was 

purely  a  question  of  inference  as  to  how  and  from  what  tin' 
bodies  originated.  Further,  if  the  urine  showed  the  ab- 
sence  of  these  same  bodies,  then  we  naturally  inferred  that 
they  were  either  completely  destroyed  or  transformed  into 
-one-  otlnr  body,  the  method-  of  which  were  likewise  enig- 
matical.    The  gaps  and  guesses  of  Foster  were  met  with 


12  SOME    PROBLEMS    OF 

at  every  turn  in  any  attempt  to  trace  out  systematically  the 
changes  of  intermediary  metabolism. 

Modern  methods  and  recent  acquirements  in  knowledge 
are  both  well  illustrated  in  what  has  been  accomplished  in 
the  study  of  purin  metabolism.  Nucleoproteids  of  various 
kinds  are  conspicuous  constituents  of  all  cells  ;  they  are 
found  in  all  tissues,  in  all  glandular  organs,  and  their  wide- 
spread distribution  may  be  taken  as  evidence  of  their  great, 
physiological  importance.  Their  metabolism  must  of  ne- 
cessity be  a  conspicuous  feature  in  the  changes  taking  place 
in  all  glandular  organs.  Chemical  study  has  shown  that 
nucleoproteids  by  simple  hydrolysis  with  mineral  acids  in  a 
flask  can  be  broken  down  into  some  form  of  proteid,  phos- 
phoric acid  and  one  or  more  purin  bases,  such  as  adenin, 
guanin,  xanthin  and  hypoxanthin.  Further,  chemical  con- 
stitution would  lead  to  the  inference,  verified  by  repeated 
experiment,  that  these  purin  bodies  can  be  readily  converted 
into  uric  acid.  Do  such  reactions  take  place  in  the  body; 
and,  if  so,  by  what  agencies  are  they  brought  about? 

If  such  glands  as  the  thymus,  suprarenal,  spleen,  etc., 
are  subjected  for  some  time  to  self-digestion  at  body-tem- 
perature in  the  presence  of  an  antiseptic,  it  can  readily  be 
demonstrated  thnt  certain  chemical  changes  occur.  Thus, 
in  the  case  of  the  thymus,  large  amounts  of  xanthin  and  a 
small  amount  of  hypoxanthin,  together  with  uracil,  are 
found  in  the  fluid.  With  the  suprarenal,  large  quantities 
of  xanthin  and  a  small  quantity  of  hypoxanthin  are  found.* 
With  both  of  these  glands,  however,  guanin  and  adenin 
are  entirely  lacking.  In  the  self-digestion  of  the  spleen, 
on  the  other  hand,  guanin  is  formed  abundantly,  also  hypo- 
xanthin, while  adenin  and  xanthin  are  wanting.  These 
results  are  quite  different  from  what  is  found  when  the 
glands  or  their  respective  nucleoproteids  are  boiled  with  acid. 
In  other  words,  when  mineral  acids  are  used  as  the  hydro- 

*  "Walter  Jones:  Ueber  die  Selbstverdauung  von  Nucleoproteiden. 
Zeitschrift  fiir  physiologische  Chemie,  Band  42,  p.  34,  1904. 


INTERMEDIARY    METABOLISM.  13 

lyzing  agents,  then  the  tissue  nucleoproteids  yield,  as  a 
rule,  guanin  and  adenin,  but  by  autolysis  xanthin  and 
hypoxanthin  are  the  conspicuous  bases.*  This  difference 
in  the  result  by  hydrolysis  with  acid  and  by  autolysis  is  due 
to  the  fact  that  in  autolysis  the  changes  induced  are  owing 
to  the  presence  of  specific  intra-cellular  ferments,  j"  which 
have  the  power  of  acting  upon  certain  of  the  purin  bodies 
transforming  them  into  other  related  substances. 

Thus,  in  the  self-digestion  of  the  pancreas  in  an  alkaline 
medium  large  amounts  of  xanthin  and  hypoxanthin  are 
found  as  the  end  products  of  the  autolysis.  Guanin  and 
adenin  are  no  doubt  also  formed,  but  they  are  gradually 
converted,  into  xanthin  and  hypoxanthin  by  intra-cellular 
ferments.  If  pure  guanin  itself  is  placed  in  a  mixture 
containing  finely  divided  pancreas,  with  chloroform  to 
prevent  putrefaction,  and  the  mixture  kept  at  40°C.  for 
some  time,  the  guanin  is  slowly  but  surely  converted  into 
xanthin,  until  in  time  it  is  wholly  replaced  by  the  latter 
base.  The  ferment  or  enzyme  that  brings  about  this  trans- 
formation is  called  guanase,\  and  is  likewise  present  in 
the  thymus  and  adrenals,  but  is  absent  from  the  spleen. 
A  corresponding  intra-cellular  enzyme,  known  as  adenase, 
and  which  transforms  adenin  into  hypoxanthin,  is  likewise 
present  in  the  thymus,  adrenals,  pancreas  and  liver. § 
These  two  ferments  are  true  hydrolyzing  agents,  the  chem- 
ical reactions  involved  being  quite  simple: 

C&H5N50  +  II2U     =     C6H4N402  4-  NH3 
guanin  xanthin 

c6n6x5  +  n2o       =    c5h4n4o  +  NHa 

adenin  bypoxantbin 

In  both  of  these  cases  it  is  to  be  noted  that  there  is  not 

only  a  taking  on  of  water,  under  the  influence  of  the  enzyme, 

*  Compare   Levene:    The    Autolysis   of   Animal   Organs.    American 
Journal  of  Physiology,  VoL  12,  i>.  276,  1904. 
t  Jones  and  Partridge:     Deber  die  Guanase.    Zeitschrift  fur  physiolo- 
Chemie,  Band  12,  p.  348,  1904. 
Jones  and  Partridge  :   Loc.  oit. 
§  Be  id  Winternitz:     Ibid.,  Band  44,  p.  I. 


14  SOME    PROBLEMS    OF 

with  a  retention  of  the  oxygen,  but  there  is  also  a  giving 
off  of  ammonia,  by  which  the  transformation  is  made  pos- 
sible. The  real  essence  of  the  reaction  is  best  shown  by 
use  of  the  constitutional  formulas,  whereby  can  be  seen  the 
full  extent  of  the  change  which  is  effected  : 


HN  -  CO 

1         1 

HN   -    CO 

1           1 

H2N.C       C-NH             +  H20 

=     CO      C  -  NH            +  NHa 

N  _  C  -  N^  Cti 

1           II            \  CH 
HN   -    C  -  N^ 

Guanin 

Xan  thin 

N  =  C.NH2 
1           1 

HN  -CO 

1         | 

HO         C-NH             +  H,0 

=       HC       C  -  NH            +  NH3 

N    -    C  -  N^- 

II        II            \  CH 
.   N  -  C  - K> 

Aclenin 

Hypoxanthiu 

Expressed  in  different  language,  these  enzymes  are  able 
to  transform  the  two  amino-purins  into  the  corresponding 
oxypurins  xanthin  and  hypoxanthin  ;  i.  e.,  they  are  typical 
deamidizing  ferments,  destroying  the  NH2  group  of  the 
adenin  and  guanin. 

Again,  it  is  possible,  as  Schittenhelm*  has  shown,  to 
prepare  from  the  spleen  simple  extracts,  free  from  all  tissue 
elements,  that  are  capable  of  transforming  these  purin  bodies 
into  uric  acid.  From  such  extracts,  the  enzyme  which  is 
the  active  agent  in  the  oxidation  can  be  separated  by  simple 
chemical  means,  and  the  purin  bases  can  be  transformed 
quantitatively  into  uric  acid  by  its  action.  The  conversion 
of  xanthin,  for  example,  into  uric  acid  is  purely  a  process 
of  oxidation  brought  about  by  a  typical  intra-cellular  oxi- 
dase, the  reaction  being  as  follows  :   < 

HN    -    C  HN    -    CO 

CO       C  -  NH  +     0     =  CO       C  -  NH 

I  II  \  CH  I  II  \  CO 

HN    -    C       N/  HN    -    C   NH/ 

Xanthin  Uric  acid 

*  Ueber  die  Ferments  des  Nucleinstoffwechsels.  Zeitschrift  f.  physio- 
logische  Chemie,  Band  43,  p.  228.  See  also  Schittenhelm  :  Ueber  die 
Harns'aurebildung  in  Gewebsauszugen.     Ibid.,  Band  42,  p.  250. 


INTERMEDIARY    METABOLISM.  15 

Schittenhelm*  has  already  demonstrated  that  this  oxi- 
dizing- enzyme  is  present  in  the  liver,  spleen,  lungs  and 
muscle,  but  is  absent  from  the  thymus,  intestine,  blood  and 
kidneys,  and  Burian  has  given  to  the  ferment  the  name  of 
"  xanthin oxidase." 

Another  interesting  fact  to  be  brought  forward  in  this 
connection  is  the  existence  of  a  specific  intra-cellnlar  enzyme 
appropriately  termed  nuclease,  which  has  the  power  of 
liberating  the  purin  bases  from  their  combination  as  a  com- 
ponent part  of  tissue  nucleoproteids,  or  more  specifically 
of  the  contained  nucleic  acids.  It  has  long  been  known 
that  nucleoproteids,  nucleins  and  nucleic  acid  when  fed 
cause  at  once  an  increased  output  of  uric  acid,  and  it  has 
been  clearly  recognized  that  uric  acid  as  a  product  of  meta- 
bolism must  result  from  the  transformation  of  the  nuclein 
bases  which  are  so  conspicuous  in  the  nucleins  and  nucleic 
acid  ;  but  as  to  how  the  uric  acid  was  formed  in  the  body 
could  only  be  conjectured.  Now,  however,  the  matter  is 
made  quite  clear,  and  we  see  how  various  intra-cellular 
enzymes  working  one  after  the  other  are  able  gradually  to 
evolve  uric  acid  from  tissue  nucleoproteids.  Under  the 
influence  of  a  nuclease,  nucleic  acid  is  split  up  with  liber- 
ation of  the  free  nuclein  bases,  then  by  the  action  of  a 
deamidizing  enzyme  guanin  and  adenin  are  transformed 
into  xanthin  and  hypoxanthin  respectively.  Further,  by 
the  action  of  the  oxidase  just  referred  to,  hypoxanthin  is 
oxidized  to  xanthin,  and  the  latter  is  converted  into  uric 
acid.  .Moreover,  it  is  worthy  of  emphasis  that  these  enzymes 
are  not  distributed  indiscriminately,  but  are  confined  to 
specific  organs  or  tissue-,  as  has  already  been  indicated. 
Finally,  it  is  to  be  noted  that  there  Is  another  tissue  oxi- 
dase  —  contained  so  far  as  is  known  at  present  in  the  kid- 
ney-, liver,  muscle,  and  perhaps  the  marrow  of  bones 
(Schittenhelm)  —  which  has   the   power  of  oxidizing  and 

*  Loe.  cit.     Band  ■»■'{,  p.  286. 


16  SOME    PROBLEMS    OF 

thus  destroying  uric  acid.  Here,  then,  we  have  four  dis- 
tinct enzymes  or  intra-cellular  ferments,  more  or  less  re- 
sponsible agents  for  the  production  and  presence  of  uric 
acid  in  the  body.  The  various  steps  in  the  intermediary 
metabolism,  by  which  this  substance  results  are  made  quite 
clear  and  we  see  how  specific  intra-cellular  enzymes,  formed 
by  the  tissue  cells,  are  responsible  for  the  chemical  changes 
induced. 

By  all  students  of  metabolism,  the  two-fold  origin  of  uric 
acid  —  endogenous  and  exogenous  —  is  well  understood. 
It  is  equally  well  known  that  in  the  origin  of  uric  acid  from 
outside  materials,  free  and  combined  purin  compounds  are 
equally  effective  ;  i.  e.,  nuclein-containing  foods  and  nitro- 
genous extractives  of  the  xanthin  type.  By  the  processes 
of  metabolism,  in  which  the  intra-cellular  enzymes  referred 
to  are  the  active  agents,  uric  acid  is  formed,  and  eventually 
appears  in  the  urine.  It  is  evident,  however,  that  exo- 
genous uric  acid  cannot  be  controlled  wholly  by  the  char- 
acter and  quantity  of  the  food  consumed.  To  be  sure, 
avoidance  of  purin-containing  foods  will  necessarily  result 
in  a  greatly  diminished  production  of  uric  acid,  but  we  must 
not  overlook  the  part  which  the  uric  acid-oxidizing  ferment 
plays  in  the  destruction  of  this  substance  in  the  tissues  of 
the  body.  As  has  already  been  pointed  out,  this  peculiar 
oxidase  has  been  found  by  Schittenhelm  in  the  liver,  muscle, 
kidneys,  and  perhaps  in  the  bone  marrow,  and  it  is  easy  to 
see  how  the  content  of  uric  acid  in  the  blood,  lymph  and 
urine  may  be  determined  as  much  by  the  relative  activity 
of  this  oxidase,  as  by  the  activity  of  the  nuclease,  amidase 
and  oxidase  which  produce  uric  acid  from  the  purin-con- 
taining foods.  It  is  perfectly  clear  that  inhibition  of  the 
oxidizing  action  of  the  uric  acid-destroying  enzyme  may  be 
as  effective  in  bringing  about  a  high  content  of  uric  acid  as 
increased  production  of  uric  acid.  We  have  no  means  at 
present  of  judging  the  relative  activity,  under  normal  meta- 


INTERMEDIARY    METABOLISM.  17 

bolic  conditions,  of  these  two  somewhat  divergent  factors, 
but  I  believe  that  the  conspicuous  increase  of  uric  acid 
noticed  under  many  conditions  of  life  is  clue  as  much  or 
more  to  increased  inhibition  of  the  oxidation  of  uric  acid  as 
to  augmented  production  of  uric  acid.  This  is  conspicu- 
ously true  in  the  influence  exerted  by  alcoholic  drinks  on 
the  uric  acid-content  of  the  blood  and  urine. 

Recent  work  carried  on  in  the  writer's  laboratory*  has 
shown  quite  conclusively  that  in  man  the  ingestion  of  alco- 
holic fluids  with  purin-containing  foods  increases  at  once 
the  output  of  uric  acid  in  the  urine.  Alcohol,  however, 
does  not  produce  this  result  when  taken  with  a  light  diet 
or  one  free  from  purin  compounds.  In  other  words,  alcohol 
influences  only  the  uric  acid  of  exogenous  origin,  in  con- 
formity witli  the  well-known  gouty  tendencies  of  high  pro- 
teid  feeding  combined  with  consumption  of  alcoholic  fluids. 
Alcohol  is  well  understood  to  interfere  with  the  oxidative 
processes  of  the  liver,  and  it  is  more  than  probable  that  its 
influence  on  the  uric  acid  content  of  the  blood  lies  in  the 
direction  of  inhibiting  the  action  of  the  oxidase  which,  pres- 
ent in  the  liver  and  other  tissues,  normally  destroys  or 
oxidizes  a  certain  proportion  of  the  uric  acid  formed.  This 
being  true,  we  see  another  illustration  of  so-called  perverted 
metabolism  due  entirely  to  a  change  in  the  rate  of  action 
of  an  intra-cellular  oxidase. 

In  any  reference  to  the  origin  of  uric  acid  in  the  body, 
too  much  stress  cannot  be  laid  upon  the  easy  convertibility 
of  the  free  purin  bases  adenin,  guanin,  hypoxanthin  and 
xanthin  into  uric  acid,|  by  virtue  of  the  action  of  the  intra- 
cellular enzymes  present  in  so  many  of  the  organs  and 
tissues.      In   the   ordinary  foodstuffs,    however,  as   in    meat 

:    The  Effect  of  Alcohol  and  Alcoholic   Fluids  upon  the 
id  In  Mni.    America!  Journal  of  Physiology,  vol.  L2, 
p.  18. 

fSee  Kriiger  and  Schmid:    Dii    Bntatehung  der  KarnRflure  auH  freien 
Paxil]  /'.itschrif't  I',  physiologische  Chexnie,  Band  34,  p,  549. 


18  SOME    PROBLEMS    OF 

broth,  it  is  the  oxypurins  hypoxanthin  and  xanthin  that  the 
body  has  to  deal  with  mainly.  These  are  quickly  oxidized 
to  uric  acid  which  may  then  be  excreted,  or  a  portion  may 
undergo  oxidation  to  urea  or  other  products.  When,  on 
the  other  hand,  combined  purins  are  introduced,  as  in  the 
nucleins  and  nucleoproteids,  adenin  and  guanin  are  liberated 
by  the  action  of  nuclease.  These  bodies  are  amino-purins, 
and  their  continuance  unchanged  depends  upon  the  presence 
and  action  of  the  two  enzymes  adenase  and  guanase.  If 
the  latter  are  present  and  active  in  normal  degree,  we  can 
conceive  of  a  ready  conversion  into  hypoxanthin  and  xanthin 
and  then  into  uric  acid.  But  if  these  .enzymes  are  lacking 
or  are  inhibited  in  their  action,  then  the  two  amino-purins 
will  float  about  unaltered  for  a  time  at  least.  May  we  not 
find  in  this  possibility  an  explanation  for  certain  disturbed 
conditions  of  the  body,  especially  of  the  kidneys,  since  ex- 
periments have  shown  that  adenin  in  the  case  of  dogs,*  and 
in  rabbitsf  when  larger  doses  are  given,  is  liable  to  produce 
anatomical  alterations  in  the  kidneys,  particularly  of  the 
tubules,  accompanied  by  peculiar  deposits  in  the  kidney 
tissue  of  spheroliths  of  uric  .acid  and  ammonium  urate, 
which  evidently  cause  irritation  and  marked  alterations  of 
structure.  Here,  again,  we  see  suggested  a  threatened 
perversion  of  metabolism  through  possible  absence  or  inhi- 
bition of  an  intra-cellular  enzyme. 

Uric  acid  of  endogenous  origin  is  as  much  a  product  of 
enzyme  action  as  that  which  is  derived  from  the  purin 
compounds  of  the  ingested  food.  It  is  well  known  that  the 
elimination  of  uric  acid  does  not  cease  during  fasting,  or 
with  a  diet  free  from  purin  compounds.  The  amount, 
however,   is  greatly  reduced  when  purin-containing  foods 

*  Minkowski :  Untersuchungen  zur  Physiologie  und  Pathologie  der 
Harnsaure  bei  Saugethieren.  Archiv  f.  exper.  Pathol,  und  Pharm.,  Band 
41,  p.  37o. 

f  Schittenhelm  :  Das  Verhalten  von  Adenin  und  Guanin  im  thierischen 
Organismus.     Ibid.,  Band  47,  p.  432. 


INTERMEDIARY    METABOLISM.  19 

are  excluded  from  the  diet.  Many  investigators*  have 
shown  experimentally  that  there  is  a  certain  degree  of  con- 
stancy in  the  output  of  uric  acid  on  a  non-purin  diet,  even 
when  there  are  wide  variations  in  the  quality  and  quantity 
of  the  purin-free  food.  Various  careful  experiments,  cov- 
ering fairly  long  periods  of  time,  carried  on  in  our  laboratory 
by  Dr.  E.  W.  Kockwoodf  on  men  taking  only  purin-free 
food,  such  as  milk,  wheat  bread,  butter,  cheese,  cereal, 
fruit,  etc.,  showed  a  daily  output  of  uric  acid  averaging 
0.3 — 0.4  gram.  Further,  it  was  observed,  in  conformity 
with  the  thesis  of  Burian  and  Schur,  that  a  given  individual 
shows  a  certain'  degree  of  constancy  in  the  daily  excretion 
of  uric  acid.  In  other  words,  the  elimination  of  endogenous 
uric  acid  is  constant  for  each  individual ;  a.  e.,  it  is  an  indi- 
vidual factor  dependent  perhaps  in  part  upon  the  weight 
of  the  body  or  the  contained  tissues  and  organs.  It  was  a 
noticeable  fact  that  the  results  obtained  were  not  influenced 
in  any  measurable  degree  by  the  extent  of  muscular  activity. 
As  to  the  origin  of  this  endogenous  uric  acid,  it  has  long 
been  taken  for  granted  that  it  must  come  in  part  from  the 
breaking  down  or  metabolism  of  the  nucleoproteids  of  the 
tissue  cells,  by  the  action  of  the  same  agencies  that  are 
effective  in  the  formation  of  exogenous  uric  acid.  There 
are,  however,  other  possible  methods  not  to  be  entirely 
overlooked  :  viz.,  the  possibility  of  a  synthetical  production 
of  the  acid  in  the  liver  or  elsewhere,  and  also  the  possibility 
of  some  other  antecedent  than  the  nucleoproteids  of  the 
glandular  organs,  leucocytes,  etc.,  serving  as  the  direct 
mother  substance  in  its  formation.  Knowing  the  fate  of 
the    nucleoproteids  of  the   food  and   the  marked   influence 

*  Burian  and  Schur:     Archiv.  f.  die  gesammte  Physiologie,  Bund  80, 
p.  2*1 ;  alao,  Band  87,  p.  239. 

ikandinavidchefl  A-Hiiv  fur  Phyaiologie,  Hand  11,  ]>.  132. 
Wiener:    Ergebninue  der  Phyeiologie,  1902,  i,  Part  L,  p.  858;  Ibid., 
I  ,  p.  877. 

•  l        Elimination   of  Endogenous  Uric  Acid.    American  Journal  of 

ology,  vol.  12,  p, 


20  SOME    PROBLEMS    OF 

these  exert  upon  the  elimination  of  uric  acid,  reinforced  by 
the  abundant  experimental  evidence  that  both  free  and 
combined  purin  bases  when  ingested  are  transformed  into 
uric  acid,  there  has  been  little  question  that  the  endogenous 
uric  acid  must  be  derived  from  the  breaking  down  of  the 
nucleoproteids  of  the  rissue  cells.  Indeed,  there  has  been 
some  disposition  to  take  the  amount  of  endogenous  uric 
acid  eliminated  as  a  measure  of  the  chemical  activity  or 
disintegration  of  tissue  elements.  This  view,  however,  has 
quite  recently  received  a  severe  shock  in  the  results  of  some 
experiments  recorded  by  Burian,*  in  which  he  shows  quite 
conclusively  that  only  a  very  small  amount  of  the  endo- 
genous uric  acid  has  its  origin  in  the  nucleoproteids  of 
disintegrating  tissue  cells  or  leucocytes,  the  larger  part 
coming  from  quite  a  different  source,  viz.,  from  the  purin 
base  hypoxanthin,  which  is  continually  being  formed  as  a 
metabolic  product  of  living  muscle  tissues.  Still,  as  already 
stated,  muscular  work,  which  naturally  means  increased 
muscular  metabolism,  has  not  appeared  to  cause  any  meas- 
urable increase  in  the  output  of  uric  acid.  This  may  be 
true,  according  to  Burian,  with  the  24  hours'  urine,  but  it 
is  not  the  case  when  the  urine  is  examined  in  hourly  periods, 
for  he  finds  that  after  vigorous  muscular  exercise  in  the  case 
of  fasting  individuals,  where  the  hourly  excretion  of  uric 
acid  is  fairly  constant,  there  is  a  marked  increase  in  the 
output  of  uric  acid  through  the  urine,  the  maximum  excre- 
tion showing  itself  in  the  second  hour  after  cessation  of  the 
work,  enduring  for  an  hour  or  longer,  then  slowly  sinking 
below  the  normal.  This  fall  in  the  rate  of  excretion  thus 
balances  in  a  measure  the  temporary  increase,  and  explains* 
why  examination  of  the  24  hours'  urine  has  failed  to  afford 
evidence  of  this  peculiar  influence. 

This  observation  of  Burian  renders  probable  an  intimate 

*  Die  Herkunft  der  endogenen  Harnpurine  bei  Mensch  und  Saiigetier. 
Zeitsehrift  f.  physiologische  Chemie,  Band  43,  p.  532. 


INTERMEDIARY    METABOLISM.  21 

relationship  between  muscle  metabolism,  the  formation  or 
liberation  of  a  purin  base  in  the  muscle,  and  its  consequent 
conversion  into  uric  acid  by  the  intracellular  xanthinoxidase. 
Further,  the  same  investigator  has  shown  that  by  perfusing 
a  mixture  of  Ringer's  solution  and  fresh  dog's  blood  through 
the  hind  leg  of  a  recently  killed  dog,  the  muscle  fibres  being 
maintained  in  a  state  of  rest,  the  blood  will  gradually  show 
the  presence  of  uric  acid ;  while  if  the  muscles  are  stimu- 
lated by  an  induction  current  for  an  hour  or  so,  then  the 
circulating  blood  shows  an  increase  of  purin  material,  and 
the  living  muscle  tissue  itself  shows  an  increased  content 
of  hypoxanthin  during  the  period  of  "  work."  It  is  obvious 
from  these  statements  that  the  muscle  or  the  blood  must 
contain  xanthinoxidase  to  convert  the  liberated  oxypurin 
into  uric  acid.  This  is  indeed  true  of  the  muscle,  for  an 
extract  of  dog's  muscle,  like  an  extract  of  the  liver  or  spleen, 
will  transform  to  uric  acid  any  oxypurin  added,  thus  afford- 
ing satisfactory  proof  that  the  muscle  contains  a  specific 
intra-cellular  oxidase.  Further,  there  is  evidence  that  the 
muscle  also  possesses  the  power  of  decomposing  uric  acid. 
There  is  thus  opened  up  a  new  chapter  in  purin  meta- 
bolism, bearing  upon  the  endogenous  production  of  uric 
acid.  In  the  resting  state,  muscle  is  continually  giving 
up  to  the  blood  a  certain  amount  of  uric  acid  formed  at  the 
expense  of  the  hypoxanthin  which  originates  within  its  own 
tissue.  The  oxidation  of  the  purin  base  to  uric  acid  is 
accomplished  by  the  specific  oxidase  which  the  muscle  it- 
self contains,  but,  as  Uurian  points  out,  this  enzyme  must 
be  bo  located  that  the  hypoxanthin  is  converted  into  uric 
a<-ii|  ju-t  as  it  is  passing  from  the  muscle  fibre  into  the  blood 
or  Lymph,  since  muscle  itself  never  contains  any  uric  acid, 
only  purin  base.  Further,  it  is  to  be  understood  that  a 
certain  amount  of  the  uric  acid  i«  at  once  decomposed  by 
the  action  of  the  other  oxidizing  ferment  which  destroys 
this  acid.     Finally,  Burian  calls  attention  to  the  fact  that 


22  SOME    PROBLEMS    OF 

since  the  hypoxanthin-content  of  the  muscles,  in  spite  of 
the  continuous  formation  and  withdrawal  of  uric  acid,  re- 
mains in  general  constant,  it  follows  necessarily  that  mus- 
cles during  rest  are  continually  forming  new  hypoxanthin 
as  a  normal  product  of  their  own  metabolism.  During 
activity,  the  formation  of  hypoxanthin  in  muscle  is  accele- 
rated, while  at  the  same  time  there  is  a  corresponding  in- 
crease in  the  output  of  the  purin  body  from  the  muscle, 
the  action  of  the  xanthinoxidase  being  doubtless  stimulated 
by  the  local  deficiency  of  oxygen  concomitant  with  the  in- 
creased muscular  activity,  and  as  a  final  result  there  is  an 
increased  production  of  uric  acid.  What  proportion  of  the 
thus  formed  uric  acid  appears  in  the  urine  we  have  at  pres- 
ent no  definite  information,  for  we  do  not  know  in  what 
degree  the  formed  acid  is  further  decomposed. 

Assuming  the  correctness  of  the  views  just  expressed,  it 
is  evident  that  muscle  tissue  takes  a  new  position  in  the 
body  as  a  uric  acid-producing  center.  The  tissue,  it  is 
true,  does  not  differ  from  other  tissues  or  organs  as  a  depot 
for  the  specific  oxidase,  but  unlike  the  other  tissues  it  is 
constantly  producing,  both  in  rest  and  in  activity,  an  oxy- 
purin  ready  for  direct  transformation.  In  the  other  uric 
acid-producing  centers,  activity  is  more  or  less  intermittent, 
being  dependent  primarily  upon  the  advent  in  the  food  of 
free  or  combined  purin  bodies  upon  which  the  intra-cellular 
amidases  and  oxidases  can  act.  Burian  considers,  on  the 
strength  of  his  experimental  results,  that  endogenous  uric 
acid  owes  its  origin  mainly  to  these  metabolic  changes  in 
muscle,  and  that  only  a  very  small  proportion  of  the  endo- 
genous acid  is  derived  from  the  nucleoproteids  of  the  disin- 
tegrating tissue  cells.  Again,  experimental  evidence*  is 
strongly  opposed  to  the  view  that  there  is  any  synthetical 
production  of  uric  acid  in  the  animal  body ;  the  only  way 

*  Burian :  Ueber  die  oxydative  und  die  vermeintliche  synthetische 
Bildung  von  Hamsaure  in  Hinderleberauszug.  Zeitschrift  f.  physiologische 
(Jhemie,  Band  43,  p.  4  97. 


INTERMEDIARY    METABOLISM.  23 

at  present  known  in  which  the  exogenous  uric  acid  can  be 
increased  in  amount,  being-  feeding  with  tree  juirin  bases,  or 
with  nucleoproteid-containing  foods  in  which  combined 
purin  bodies  are  present.  In  other  words,  uric  acid  owes 
its  origin  entirely  to  processes  of  enzymatic  oxidation. 

We  may  advantageously  pause  here  for  a  moment  to 
consider  the  possible  bearing  of  these  facts  upon  so-called 
.oxidation  within  the  body.  We  have  seen  how  in  the  pro- 
cesses discussed,  oxidation  is  dependent  upon  specific  fer- 
ments or  enzymes,  and  we  further  understand  that  the 
intermediary  products  formed  are  definite  bodies  because  of 
the  specific  nature  of  the  active  enzymes,  and  secondly,  be- 
cause of  the  chemical  nature  of  the  substances  acted  upon. 
In  other  words,  oxidation  in  intermediary  metabolism  be- 
gins to  take  on  the  shape  of  a  series  of  well-defined  chemi- 
cal processes  in  which  chemical  constitution  and  specific 
enzyme  action  are  the  predetermining  causes.  In  the 
absence  of  the  particular  chemical  groups,  the  oxidase  is 
ineffective  to  bring  about  oxidation,  or  given  the  proper 
compound  or  mother  substance  in  the  absence  of  the  speci- 
fic oxidase  there  is  no  oxidation.  Oxidation  in  the  animal 
body,  therefore,  certainly  as  applied  to  intermediary  me- 
tabolism, is  no  longer  to  be  classed  with  ordinary  combus- 
tion processes.  We  rind,  on  the  contrary,  a  series  of  order- 
ly chemical  processes,  each  one  of  which  is  presided  over 
by  an  infra-cellular  enzyme,  specific  in  its  nature  in  that 
it  is  capable  of  acting  only  upon  bodies  having  a  certain 
definite  composition,  and  leading  invariably  to  a  certain  defi- 
nite result.  Further,  it  is  easy  to  see  how  perversion  or 
inhibition  of  intermediary  metabolism  may  be  engendered 
by  causes  which  act  primarily  upon  the  cells  where  the 
enzymes   in   question   have   their  origin,  or   by    influences 

which  may  bring   about    changes    in    the    environment    sur- 

rounding  the  intra-cellular  ferment ;   forjusl  ae  the  ordinary 
i-ce||nlar  digestive  enzymes  are  influenced  in  their  ac- 
I 


24  SOME    PROBLEMS    OF 

tivity  by  surrounding  conditions,  so  may  the  intra-cellular 
oxidative  enzymes  feel  the  effect  of  changes  in  their  envi- 
ronment. 

In  enzyme  action  in  general,  maximum  results  are  ob- 
tained only  when  the  enzyme  and  the  substance  to  be  acted 
upon  bear  a  certain  definite  relationship  to  each  other.  A 
proportionate  excess  of  one  over  the  other  may  modify  the 
rate  of  action,  and  where  the  substance  undergoing  change  — > 
in  intermediary  oxidation  —  is  in  relative  excess  over  the 
enzyme  there  would  seem  suggested  the  possibility  of  a 
perversion  of  the  normal  oxidative  change.  In  such  a  case 
as  this,  some  intermediary  body  —  perhaps  abnormal  in 
nature  —  might  make  its  appearance.  This  principle  in 
metabolism  is  well  illustrated  by  some  recent  experiments 
carried  on  in  our  laboratory  *  bearing  on  the  formation 
and  excretion  of  allantoin  in  the  animal  body.  Allantoin 
is  an  oxidation  product  of  uric  acid,  having  the  formula  : 

NH.     CH.     HN 

OC  <  |  >  CO 

NH.     CO    H2N 

It  is  found  in  the  urine  of  pregnant  women  and  in  the 
urine  of  newly  born  infants.  It  is  likewise  excreted  in 
large  quantities  by  dogs  after  feeding  pancreas,  thymus, 
lymphatic  glands,  or  any  other  material  rich  in  nucleic 
acid.  It  also  appears  in  the  urine  of  the  dog  and  cat  after 
feeding  relatively  large  amounts  of  uric  acid.  In  other  words, 
it  is  quite  evident  from  the  experimental  records  that  in  the 
case  of  these  animals  at  least  the  purin  bases  (and  nucleins) 
may  give  rise,  under  some  conditions,  to  allantoin  as  an 
intermediate  product  of  their  oxidation.  Ordinarily,  these 
compounds  of  the  purin  type  are  more  completely  oxidized 
in  the  system,  with  formation  of  urea,  although,  as  we 
have  seen,  a  certain  proportion  of  the  nitrogen  is  excreted 

*  Mendel,  Underhill  and  White,  American  Journal  of  Physiology,  Vol. 
8,  p.  380.  In  this  article  are  contained  references  to  a  large  number  of 
papers  bearing  on  this  subject. 


INTERMEDIARY    METABOLISM.  25 

as  uric  acid.  But  when  larger  quantities  per  kilo  of  body- 
weight  of  uric  acid,  or  of  the  antecedent  purin  compounds, 
are  introduced  or  formed  in  the  system,  the  oxidative 
enzymes  are  unable  to  bring  about  as  complete  a  decompo- 
sition of  the  purin  radicles,  and  under  such  conditions 
allantoic  escapes  as  an  end-product  of  the  incomplete  oxi- 
dation of  the  acid. 

Drugs  that  are  known  to  influence  certain  lines  of  me- 
tabolic activity  in  which  the  purin  bodies  are  concerned, 
may  well  have  their  action  explained  by  assuming  an  in- 
fluence upon  enzymatic  oxidation,  as  well  as  by  attributing 
the  effect  to  some  general  disturbance  of  functional  activity 
of  the  gland  or  tissues.  Further,  with  this  mode  of  expla- 
nation at  hand,  it  is  easier  to  understand  how  drugs  that 
bring  about  marked  pathological  conditions  may  still  be 
free  from  influence  upon  some  of  the  lines  of  functional 
activity  with  which  the  gland  or  tissue  is  associated.     Thus, 

some  experiments  recently  carried  on  in  our  laboratory 
show,*  phosphorus  which  produces  such  marked  hepatic 
degeneration  does  not  interfere  in  the  case  of  the  dog  with 
tin-  power  to  elaborate  uric  acid  during  a  diet  rich  in  purin 
compounds.  In  other  words,  the  specific  nuclease,  amidase 
and  xanthinoxidase  are  not  inhibited  in  their  action  by  the 
presence  or  influence  of  phosphorus,  but  uric  acid  is  formed 
;i-  under  normal  conditions  when  purin-containirig  foods 
are  exhibited.  Further,  other  experiments!  made  in  our 
laboratory  with  sulphonal,  a  typical  hepatic  drug,  tend  to 
-how  that  in  fasting  dogs  there  is  no  undue  formation  of 
allantoin  when  soluble  urates  are  injected  into  the  circula- 
tion, !.  e.f  the  normal  uric  acid  oxidation  is  not  interfered 
with,  even    though  the   animal   be   strongly  under  the   in- 

*    Mendel   and  Jackson:     American  Journal  of  Physiology,  Vol.   I,  p. 

■(•  Mendel  and  White:     On  the  Intermediary  Metabolism  of  the  Purin 
Production  of  Allantoin   in  the  Animal  Body.     American 
Journal  of  Physiology,  Vol.  12,  p.  93. 


26  SOME    PROBLEMS    OF 

fluence  of  the  drug.  When,  however,  animals  fed  on  pan- 
creas, i.  e.,  with  an  abundance  of  nucleoproteid,  are  treated 
with  sulphonal,  then  it  is  found  that  allantoin,  which  on 
the  above  diet  would  normally  appear  in  large  amounts,  is 
never  present  in  the  urine.  Presumably,  the  sulphonal  in 
some  way  iufluences  favorably  the  oxidation  of  the  purin 
compounds  to  uric  acid  and  urea,  and  it  is  reasonable  to 
assume  that  this  action  is  due  to  some  stimulating  influence 
upon  the  oxidases  of  the  liver  or  other  glands,  as  to  ascribe 
it  to  any  other  more  general  cause. 

We  must  not,  however,  confine  our  attention  too  long  to 
one  particular  line  of  intermediary  metabolism,  remember- 
ing that  there  are  many  other  chapters  in  nutrition  to  which 
attention  may  profitably  be  directed,  in  illustration  of  our 
main  theme.  Let  us  therefore  consider  next  some  phases 
of  the  intermediary  metabolism  of  carbohydrates  and  its 
perversions,  which  will  afford  us  opportunity  also  to  discuss 
the  formation  of  oxalic  acid,  glycuronic  acid,  etc.  It  is 
well  understood  that  under  ordinary  conditions  of  life  and 
health,  the  carbohydrates  of  our  food  and  body  tissues  are 
continually  undergoing  oxidation  with  ultimate  formation 
of  carbon  dioxide  and  water,  but  it  is  not  to  be  supposed 
that  this  oxidation  necessarily  takes  place  wholly  at  one 
step.  In  the  blood,  as  Lepine*  originally  pointed  out, 
there  is  present  a  glycolytic  ferment  or  enzyme  which  has 
the  power  of  destroying  sugar,  but  as  Kraussf  and  Arthus| 
have  shown,  this  action  of  the  blood  is  not  sufficiently  strong 
to  bring  about  the  oxidation  of  the  several  hundred  grams 
of  sugar  that  are  being  broken  down  in  the  body  each  day. 
The  discovery  by  v.  Mering§  and  Minkowski  that  extirpa- 
tion of  the  pancreas  produces  a  severe  form  of  diabetes  led 

*  Comptes  rendu,  Tome  110,  p.  742  and  p.  1314. 
t  Zeitschr.  f.  klin.  Med.,  Band  21,  p.  315. 
+  Arch,  de  Physiol.,  Tome  24,  p.  337. 

§  Diabetes  mellitus  nach  Pankreasextirpation.  Archiv  f.  exper.  Pathol, 
u.  Pharm.,  Band  26,  p.  371. 


INTERMEDIARY    METABOLISM.  27 

naturally  to  the  view  that  this  organ  normally  produces 
something,  possibly  an  internal  secretion,  failure  of  which 
rentiers  the  body  unable  to  burn  sugar.  Search  for  the 
presence  of  a  glycolytic  ferment  in  the  pancreas,  however, 
gave  negative  results.*  It  remained  for  Cohnheimf  to 
show  that  when  the  pancreas  is  combined  with  muscle  there 
is  developed  a  strong  sugar-decomposing  action.  The  pan- 
creas alone  has  no  such  power,  and  muscle  likewise  when 
taken  by  itself  shows  no  appreciable  glycolytic  action,  but 
the  two  together  have  such  power  that  5.6  grams  of  sugar 
can  be  destroyed  or  burned  by  a  kilogram  of  muscle.  If, 
Bays  Cohnheim,  we  estimate  that  an  adult  man  possesses 
40  kilograms  of  muscle,  this  tissue  influenced  by  the  action 
of  the  pancreas  is  quite  capable  of  oxidizing  over  200  grams 
of  dextrose. 

This  oxidizing  power  is  not  dependent  upon  the  presence 
of  the  tissue  cells,  but  the  active  agent  can  be  extracted 
and  the  resultant  cell-free  fluid  shows  the  same  power  of 
oxidizing  dextrose,  thus  signifying  quite  clearly  that  the 
agent  is  a  soluble  enzyme  or  ferment,  which  presumably 
resides  in  the  muscle  tissue  in  an  antecedent  form  and  is 
activated  through  some  influence  exerted  by  the  pancreas. 
The  action  is  thus  analogous  to  the  influence  exerted  by 
tin-  enterokinase  of  the  intestinal  glands,  which  has  the 
power  of  transforming  inactive  tripsinogen  into  the  active 
enzyme  trypsin,  the  proteolytic  enzyme  of  the  pancreatic 
juice.  It  i<  true  that  these  results  of  Cohnheim  have  been 
adversely    criticised    by    some    investigators,    notably    by 

Stoklasfl  and    by  Claue    and    Kmbden,  but    nevertheless   the 

general  trend  of  the  results  seems  pretty  clearly  established, 
and  it  appears  ei  idenl  that  glycolytic  action,  which  undoubt- 

•  Herzog:  Liefer)  dan  Pankreaa  ein  Dextrose  spaltendea,  alkohol  und 
kohlena&nre  bildendei  Enzym?  Hofmeiater'a  Beitrftge  zui  chemischen 
Physiologic  und  Pathologic  Band  2,  p.  102. 

•  ])  ■  Kohlehydrateverbren niing  in  den  Muakeln  und  ihre  Beeinfiusaung 
dnrch  daa  Pankreaa.     Zeitachrift  fur  phyaiologiaohe  Chemie,  Band  89,  p. 

\u«,  Band  L2,  p.  101,  and  Band  18,  p.  ~>i~. 


28  SOME    PROBLEMS    OF 

edly  occurs  in  most,  if  not  all,  of  the  active  tissues  of  the 
body,  is  due  to  soluble  enzymes,  the  activity  of  which  is 
heightened  through  the  influence  of  some  agent  or  agents 
furnished  by  the  pancreas. 

In  this  oxidation  of  sugar  by  the  tissues  of  the  body,  a 
large  proportion  of  the  sugar  burned  is  unquestionably  en- 
tirely destroyed,  but  not  always  is  the  oxidation  complete, 
and  then  intermediate  products  make  their  appearance  as  a 
sign  and  a  warning  of  physiological  processes  gone  astray. 
Incomplete  or  improper  burning  of  sugar  may  —  in  the 
absence  of  any  better  explanation  —  be  ascribed  to  lack  of 
the  specific  enzyme  or  enzymes,  or  to  lack  of  suitable  con- 
ditions for  their  proper  activation . 

The  sugar  of  the  blood,  it  will  be  remembered,  is  dex- 
trose, an  aldehyde,  having  the  formula  : 
CH2  (OH).     CH(OH).     CH  (OH).     CH  (OH).     CH  (OH).     CHO 

By  mild  oxidation,  the  aldehyde  group  (CHO)  is  changed 
into  an  acid  group    (carboxyl  group,  COOH)   and  mono- 
basic gluconic  acid  results,  viz.  : 
CH2  (OH).     CH  (OH).     CH  (OH).     CH  (OH).      CH(OH).     COOH 

By  more  energetic  oxidation,  the  dibasic  saccharic  acid 
is  formed,  viz.  : 
COOH.     CH  (OH).     CH  (OH).     CH  (OH).     CH(OH).     COOH. 

These  two  illustrations  suffice  to  show  the  readiness  with 
which  aldehyde  groups  (CHO)  and  primary  alcohol  groups 
(CH2OH)  are  oxidized  to  acid  groups  (COOH).  It 
might  be  assumed  therefore  that  all  substances  containing 
the  above  groups  would  undergo  oxidation  in  the  body 
along  the  lines  indicated,  just  as  ordinary  alcohol  when  in- 
troduced into  the  system  may  yield  aldehyde  and  acetic 
acid  when  the  oxidation  is  somewhat  restricted.  As  we 
have  tried  to  point  out,  however,  oxidation  in  the  animal 
body  is  something  more  than  a  mere  exposure  to  oxygen, 
and  it  does  not  necessarily  follow  that  all  substances  con- 


INTERMEDIARY    METABOLISM.  29 

taining  these  groups  will  be  oxidized  in  rhythmic  fashion 
in  the  body,  or  through  a  regular  series  of  successive  stages. 
The  very  fact  that  such  results  do  not  always  occur  affords 
the  best  of  evidence  that  animal  oxidation  involves  other 
factors  than  simple  oxygen  ;  i.  ?.,  is  in  harmony  with  the 
view  that  oxidation  of  a  given  substance  depends  in  large 
measure  upon  the  presence  of  specific  intra-cellular  oxidases 
which  can  attack  that  particular  substance.  This  view  is 
forcibly  illustrated  by  the  work  of  Paul  Meyer*  with  ethy- 
lene alcohol,  or  glycol,  and  its  derivatives. 

The  oxidation  products  of  glycol  that  would  naturally 
come  under  physiological  consideration  are  the  following, 
the  relationship  of  which  is  indicated  by  the  formula? : 

CH2OH  COH  COOH  COH         COH  COOH 

!  I  I  I  I 

CH20H  CH2OH  CH2OH         COH  COOH  COOH 

Ethylene  Glycol  Glycollic         Glvoxvl        Glyoxylio  iixiilic 

glycol.  aldehyde.  acid.  *  y      }  acid.  acid. 

It  has  been  found  by  Pohlf  that  glycol  or  ethylene  alco- 
hol in  the  case  of  the  dog  can  be  only  partially  burned  in 
the  body,  and  that  its  introduction  always  gives  rise  to  a 
large  production  of  oxalic  acid.  Mayer  has  found  the 
same  to  be  true  in  the  case  of  rabbits.  It  is  a  noticeable 
fact,  however,  as  pointed  out  by  Mayer,  that  when  glycol 
or  ethylene  alcohol  is  given  to  rabbits  in  moderately  large 
doses,  there  is  a  large  output  of  glycollic  acid.  In  fact, 
it  may  be  stated  that  under  the  above  conditions  about  one- 
fourth  of  the  glycol  is  oxidized  simply  to  glycollic  acid, 
while  the  presence  of  considerable  oxalate  in  the  urine  de- 
monstrates, further  oxidation  of  a  portion  of  the  glycol  to 
oxalic  acid.  With  sufficient  dosage  of  glycol,  rabbits  suc- 
cumb with  severe  haemorrhagic  nephritis,  the  glomeruli 
being  practically  occluded  with   crystals  of  calcium   oxalate 

•  Experimen telle  lieitrftge  zui  Frage  dea  Lntermediaren  Stoffwechsela 
dor  Kohlehydrate.     Zeitschrift  f.  physiologinche  Chemie,  Hand  38,  p.  135. 

t  debet  den  oxidativen  A.bbau  dei  Fettkdrper  lm  thierischen  Organis- 
mue.    Aichiv  f.  exper.  Pathol,  u.  Pharm.,  Hand  37. 


30  SOME    PROBLEMS    OF 

and  the  whole  section   of  the  kidney  tissue   showing  large 
masses  of  this  crystalline  salt. 

The  significance  of  these  facts  in  the  present  connection 
lies  in  the  probability,  as  suggested  by  Mayer,  that  this 
peculiar  oxidation  by  which  glycollic  and  oxalic  acids  result 
without  any  appearance  of  bodies  intermediate  between  these 
two,  is  due  first  to  simple  oxidation  of  the  primary  alcohol 
group  of  glycol  to  the  carboxyl  group,  thus  giving  rise  to 
glycollic  acid,  as  follows  : 

CH20H  »-*•  COOH 

I  I 

CH20H  CH2OH 

Bv  further  oxidation  of  the  so-formed  glycollic  acid,  the 
remaining  primary  alcohol  group  of  the  acid  is  similarly 
attacked  with  formation  of  oxalic  acid  as  follows  : 

COOH  COOH 

I  I 

CH2OH  »->■  COOH 

In  other  words,  we  have  here  a  striking  example  of  a 
definite  line  of  oxidative  action,  involving  an  attack  upon 
a  distinct  group  of  atoms,  with  a  complete  ignoring  of 
other  groups  which  a.  priori  are  seemingly  just  as  easy  of 
oxidation.  How  can  this  selective  action  be  accounted  for 
other  than  by  the  assumption  that  we  are  dealing  with 
specific  oxidases  which  have  an  affinity  as  it  were  for  dis- 
tinct groups  or  radicals,  reinforced  by  an  influence  exerted 
by  the  stereochemical  configuration  of  the  molecule  acted 
upon.  In  any  event,  these  results  are  a  striking  refutation 
of  the  view  that  animal  oxidation  follows  ordinary  chemical 
and  physical  laws. 

This  statement  may  be  reinforced  by  reference  to  the  re- 
sults obtained  by  Mayer*  in  his  experiments  with  glycol 
aldehyde.  This  substance  by  oxidation  would  naturally 
give  rise  to  glycollic  acid,  glyoxylic  acid  and  oxalic  acid, 
as    suggested    by    the    preceding    formulas.      If,    however, 

*  Loc.  cit.,  p.  151. 


INTERMEDIARY    METABOLISM.  31 

glycol  aldehyde  is  administered  subcutaneously  to  rabbits, 
it  is  at  once  oxidized  without  any  formation  of  bodies  inter- 
mediate between  the  aldehyde  and  oxalie  aeid  ;  glycollic 
acid  and  glyoxylic  acid,  which  might  be  expected,  are  not 
found  even  in  traces.  On  the  other  hand,  dextrose  is 
formed  in  considerable  quantity.  This  formation  of  dex- 
trose after  injection  of  glycol  aldehyde  is  not  to  be  ascribed 
to  increased  formation  of  oxalic  acid,  for  it  is  noticeable 
that  excretion  of  the  sugar  commences  within  twenty  min- 
utes after  the  aldehyde  is  introduced  and  before  any  acid 
formation  could  have  exerted  much  influence.  More  plaus- 
ible is  the  hypothesis,  suggested  by  Mayer,  that  a  certain 
proportion  of  the  glycol  aldehyde  is  directly  condensed  in 
the  organism  to  dextrose,  the  oxidative  power  of  the  organ- 
ism being  inhibited  in  some  degree  by  the  toxic  action  of 
the  aldehyde,  and  thus  permitting  a  portion  at  least  of  the 
so-formed  dextrose  to  escape  combustion  and  thus  appear 
in  the  urine.  So  here  again  we  find  evidence  of  specific 
oxidative  action  in  the  organism,  due  no  doubt  to  a  specific 
aldehydase,  combined  with  a  process  of  condensation,  both 
of  which  are  very  suggestive  in  connection  with  our  under- 
standing of  the  processes  involved  in  intermediary  carbo- 
hydrate metabolism. 

The  formation  of  oxalic  acid  in  the  body,  just  referred  to 
in  connection  with  the  oxidation  of  glycol  derivatives,  is 
worthy  of  further  consideration  in  connection  with  carbo- 
hydrate metabolism.  The  work  of  Mohr  and  Salomon* 
bae  shown  that  the  body  of  man  normally  produces  a  small 
amount  of  oxalic  acid  which  is  excreted  in  the  urine.  T^ith 
an  oxalate-free  diet,  the  daily  urine  contains  2—6  milligrams 
of  the  acid,  increased  somewhat  by  certain  foods  such  as 
gelatin.      Practically,  all  the   tissues   of  the  body  contain 

-mall    amounts    of   oxalate;     muscle    of   man,    for    example, 

•Untersuchungen  zur  Phyiologie  and  Pathologie  der  Oxalaa'urebildung 
nnd-AuMicheidang  bam  Mennchen.  Deutsch,  Archiv,  f.  klin,  Medicin,  Band 

7".  p.  , 


32  SOME    PROBLEMS    OF 

showing  6.5  milligrams  of  oxalic  acid  per  kilo  of  tissue.* 
According  to  Salkovvski,  the  spleen,  liver  and  muscle  by 
autolysis  in  the  presence  of  uric  acid  form  a  small  amount 
of  oxalic  acid.  More  pertinent,  however,  are  the  obser- 
vations of  Hildebrant  t  who  found  on  givino;  dextrose  to 
rabbits  fed  on  oats  (which  contain  lime  salts)  that  there 
was  a  very  great  increase  in  the  production  of  oxalic  acid, 
the  acid  appearing  in  the  urine  as  calcium  oxalate.  In 
other  words,  under  some  conditions  at  least,  oxalic  acid 
may  be  considered  as  an  oxidation  product  of  dextrose. 

In  this  connection,  it  is  to  be  remembered  that  many  ob- 
servations X  tend  to  show  that  in  the  incomplete  oxidation 
of  sugar  in  the  body,  glycuronic  acid  is  a  conspicuous  pro- 
duct. Thus,  in  diabetes  mellitus  there  is  frequently,  if  not 
most  generally,  an  increased  excretion  of  glycuronic  acid  ; 
a  condition  which  often  persists  even  when  in  consequence 
of  a  strict  anti-diabetic  diet,  sugar  excretion  has  entirely 
disappeared.  Moreover,  there  are  many  diseases  in  which 
sugar  rarely  appears  in  the  urine  where  glycuronic  acid  is 
present  in  increased  quantity.  Thus,  as  stated  by  Mayer, 
there  are  various  acute  febrile  conditions  in  which  increased 
excretion  of  glycuronic  acid  is  found  in  harmony  with  the 
fact  that  in  these  diseases  the  power  of  assimilation  for 
dextrose  is  inhibited  somewhat,  coupled  with  diminished 
power  of  oxidation  of  sugar,  thereby  resulting  in  a  portion 
of  the  dextrose  being  oxidized  only  to  glycuronic  acid,  while 
the  conditions  do  not  admit  of  any  excretion  of  unchanged 
sugar.  Further,  it  is  to  be  noted  that  when  a  soluble  salt 
of  glycuronic  acid  is  given  to  rabbits  there  results  a  marked 
increase  in  the  output  of  oxalic  acid,  proportional  to  the 
amount  of  glycuronate  fed.     In  diabetes,  oxaluria  is  occa- 

*  Cipollina :  Ueber  die  Oxals'aure  im  Organismus.  Berliner  klin.  Wochen- 
schrift,  1901,  p.  544. 

t  Uber  eine  experimentelle  Stoffwechselabnormit'at.  Zeitschrift  f.  phy- 
siologische  Chemie,  Band  35,  p.  141. 

J  See  especially  Paul  Mayer :  Uber  uiivolkommene  Zuckeroxydation  im 
Organismus.     Deutsche  med.  Wochenschrift,  1901,  p.  243  and  p.  262. 


INTERMEDIARY    METABOLISM.  33 

sionally  met  with,  in  harmony  with  a  preceding  .statement 
that  oxalic  acid  is  liable  to  result  from  the  incomplete  com- 
bustion of  dextrose.  The  well  known  antagonism  between 
glycosuria  and  oxaluria  frequently  observed  is  due  to  the 
fact  that  in  severe  cases  of  diabetes  the  greater  portion  of 
the  sugar  present  is  not  oxidized  at  all,  while  with  improve- 
ment in  the  assimilation  of  sugar  a  portion  is  oxidized, 
nut,  however,  to  carbon  dioxide  and  wrater,  but  simply  to 
oxalic  acid.  From  these  statements,  the  inference  may  be 
drawn  that  both  glycuronic  and  oxalic  acids  are  products 
of  the  incomplete  oxidation  of  sugar,  and  further,  that  in 
some  instances  at  least  glycuronic  acid  is  an  antecedent  or 
intermediary  body  in  the  production  of  oxalic  acid. 

Glycuronic  acid  is  unquestionably  an  important  body  in 
the  intermediary  metabolism  of  carbohydrates.  It  is  much 
more  widely  distributed  and  much  more  common  than  has 
generally  been  supposed.  It  does  not  occur  in  the  free 
state  in  the  animal  body,  but  exists  conjugated  with  various 
aromatic  substances,  notably  with  phenol,  indoxyl,  etc., 
tltese  conjugated  forms  being  normally  present  in  the  urine. 
The  introduction  of  camphor  or  chloral  hydrate  (with  which 
glycuronic  acid  combines)  into  the  system  is  followed  by  a 
marked  increase  in  the  excretion  of  glycuronic  compounds 
in  the  urine,  thus  implying  the  formation  in  the  body  of 
much  more  glycuronic  acid  than  is  indicated  ordinarily  by 
the  content  of  this  substance  in  the  urine. 

A-  to  the  origin  of  glycuronic  acid,  there  is  abundant 
experimental  evidence,  in  harmony  with  what  has  previously 
been  Stated,  that  in  rabbits  at  least  the  acid  can  be  formed 
from  dextrose.  Further,  there  is  likewise  experimental 
evidence  tending  to  show  that  in  all  probability  glycuronic 
acid  '-an  also  originate  from  proteid,  i.  e.,  from  the  car- 
bohydrate group  of  the  proteid   molecule.*     The  transfor- 

•  See  Paul  Mayer;  Neue Untersuohungen  iiber  die  GlukuronsSure,    Bi- 
1    ntralblatt,  Band  l,  p.  ■<77. 


34  SOMK    PROBLEMS    OF 

mation  which  dextrose  undergoes  when  oxidized  to  glycuronic 
acid  is  very  slight,  and  consists  simply  in  the  conversion  of 
the  primary  alcohol  group  of  the  sugar  into  the  carboxyl 
group  of  the  acid,  leaving  the  aldehyde  group  of  the  sugar 
intact,  as  indicated  by  the  following  formulae  : 
CH20H  *§h>-  COOH 

I  I 

CHOH  CHOH 

I  I 

CHOH  CHOH 

I  I 

CHOH  CHOH 

I  I 

CHOH  CHOH 

I  I 

CHO  CHO 

Dextrose  Glycuronic  acid 

A  priori^  it  might  be  expected  that  in  the  foregoing  oxi- 
dation the  very  labile  aldehyde  groupe  would  be  the  one  to 
undergo  change  with  formation  of  the  monobasic  gluconic 
acid,  but  the  facts  available  do  not  support  this  view  and 
the  conclusion  may  be  accepted  as  affording  another  evi- 
dence of  the  specific  action  of  tissue  oxidation,  in  which 
without  doubt  intra-cellular  enzymes  are  the  active  agents. 
The  evidence  at  hand,  both  experimental  and  clinical,  ren- 
ders quite  conclusive  the  view  that  glycuronic  acid  appears 
in  the  tissues  and  in  the  excretions  as  the  result  of  an  in- 
complete oxidation  of  dextrose  (both  that  which  is  derived 
from  carbohydrate  and  that  which  has  its  origin  in  the 
breaking  down  of  the  proteid  molecule),  and  consequently 
the  amount  of  this  acid  present  may  be  taken  as  a 
measure  of  the  extent  to  which  the  sugar  is  escaping  oxi- 
dation or  combustion.  Further,  it  is  to  be  understood 
that  glycuronic  acid  is  a  normal  intermediary  product  of 
carbohydrate  metabolism,  representing  perhaps  the  first 
step  in  the  breaking  down  of  sugar,  which  under  ordinary 
or  normal  conditions  progresses  to  further  stages  with  com- 
plete or  nearly  complete  disappearance  of  the  intermediary 
glycuronic  acid,  except  in  those  cases  where  further  oxida- 


INTERMEDIARY    METABOLISM.  35 

tion  is  wholly  or  in  part  inhibited.  In  the  latter  case,  the 
amount  of  glycuronic  acid  in  the  circulation  is  greatly  in- 
creased and  so  likewise  the  various  aromatic  substances, 
which  under  ordinary  circumstances  are  combined  with  it 
in  small  degree,  are  conjugated  in  larger  quantities,  thereby 
leading  to  an  increased  excretion  of  phenol,  indoxyl  and 
other  glycuronates,  with  a  corresponding  decrease  in  the 
excretion  of  ethereal  sulphates. 

If  glycuronic  acid  represents  the  first  stage  in  the  inter- 
mediary metabolism  of  sugar,  then  the  dibasic  saccharic 
acid  might  well  be  suspected  as  the  second  product  in  a 
progressive  oxidation,  where  the  aldehyde  group  of  glycu- 
ronic acid  is  replaced  by  the  carboxyl  group  as  indicated 
in  the  following  formula?,  a  view  which  is  supported  by  ex- 
perimental evidence  : 

COOH  COOH 

I  I 

CHOH  CHOH 

I  I 

CHOH  CHOH 

I  I 

CHOH  CHOH 

I  I 

CHOH  CHOH 

I  I 

CHO      ■-*"      COOH 

Glycuronic  acid  Saccharic  acid 

Comparison  of  the  structural  formula  of  saccharic  acid 
COOH 
with  that  of  oxalic  acid  shows  how   easily   by  one 

COOH 

or  more  changes  the  latter  acid  may  be  funned  by  progres- 
sive oxidation,  in  harmony  with  the  fact  already  mentioned 
that  administration  of  glycuronic  acid  is  followed  by  an 
increased  excretion  of  oxalic  acid,  accompanied  by  accumu- 
lation of  oxalic  acid  in  the  liver.  The  liver  is  unquestion- 
ably one  of  the  places  where  glycuronic.  acid  is  oxidized  to 
oxalic  acid,  since  it  is  easy  to  demonstrate  by  digestion 
experiments  with  comminuted  liver  tissue  the  transforma- 
tion  of  the  former  acid  to  oxalic  acid  ;  an  observation  of 


36  SOME    PROBLEMS    OF 

obvious  importance  in  intermediary  metabolism.  Finally, 
it  may  be  mentioned  that  there  is  some  ground  for  the 
belief  that  a  part  of  the  dextrose  in  the  body  is  normally 
oxidized  without  first  passing  through  the  intermediary 
stage  of  glycuronic  acid.  How  large  this  fraction  may  be 
cannot  be  said,  but  in  any  event  the  glycuronic  acid  that 
is  formed  is  further  oxidized  with  subsequent  formation  of  a 
variable  amount  of  oxalic  acid. 

As  we  study  these  various  intermediary  steps  and  stages 
in  carbohydrate  metabolism,  we  cannot  avoid  being  im- 
pressed more  and  more  fully  with  the  general  principle 
that  the  appearance  of  the  so-called  abnormal  products  of 
carbohydrate  degradation,  like  sugar  itself,  is  due  not  so 
much  to  perverted  metabolic  action  as  to  inhibition  of  one 
or  more  of  the  normal  oxidative  processes  by  which,  under 
normal  conditions,  these  various  intermediary  products  are 
further  oxidized  and  destroyed.  Incomplete  or  improper 
burning  of  sugar  is  responsible  for  the  presence  of  these 
symbols  of  disturbed  nutrition.  Under  ordinary  conditions 
they  are  quickly  oxidized  from  stage  to  stage,  through  the 
agency  of  specific  oxidases  or  other  ferments,  until  the  final 
end-products  are  reached.  Disturbance  of  function  may 
therefore  be  ascribed  in  ultimate  analysis  to  lack  of  the 
specific  enzyme,  or  to  lack  of  suitable  conditions  for  the 
proper  action  of  the  enzyme.  The  burning  of  sugar  in  the 
body  is  as  much  dependent  upon  the  progressive  action  of 
specific  oxidizing  enzymes  as  the  hydrolysis  of  carbohydrates 
in  general  is  dependent  upon  the  action  of  amylolytic  en- 
zymes. This  principle  is  well  illustrated  by  some  experi- 
ments recently  carried  on  in  our  laboratory  by  Mr.  P.  H. 
Mitchell,  in  which  it  was  found,  for  example,  that  soluble 
erythrodextrin  when  injected  subcutaneously  or  intraperi- 
toneally  was  thrown  out  through  the  urine  in  large  amount 
as  achroodextrin ;  i.  e.,  essentially  unchanged.  Though 
readily  oxidizable,  by  this  method  of  introduction  the  dex- 


INTERMEDIARY    METABOLISM.  36 

0 

trin  escaped  contact  with  the  enzymes  which  under  other 
conditions  would  have  quickly  oxidized  and  destroyed  it. 
Similarly,  Mr.  Mitchell  found  that  the  carbohydrate  inulin 
introduced  in  like  manner  could  be  recovered  in  the  urine 
to  the  extent  of  70  per  cent,  wholly  unchanged.  Dr.  Paul 
Mayer  has  reported  a  similar  experience  with  glycogen,  re- 
covering 50  per  cent,  of  the  carbohydrate  essentially  un- 
changed in  the  urine  after  subcutaneous  injection.  In 
other  words,  the  specific  enzymes,  the  intra-cellular  ferments 
of  the  tissues,  as  well  as  the  amylolytic  enzymes  of  the 
digestive  juices,  must  have  proper  opportunity  for  action  if 
the  successive  steps  of  carbohydrate  metabolism  or  oxida- 
tion are  to  be  successfully  carried  out. 

Again,  in  many  forms  of  experimental  diabetes  such,  for 
example,  as  we  have  been  in  the  habit  of  speaking  of  as 
due  to  "  insults  "  offered  to  the  pancreas,  where  such  sub- 
stances as  piperidin,  potassium  cyanide,  morphia,  coniin, 
nicotin,  curare,  ether,  chloroform,  etc.,  produce  marked 
hyperglycemia  and  glycosuria,  the  explanation  now  offered* 
is  that  these  drugs  do  not  have  any  specific  action  upon  any 
particular  gland,  like  the  pancreas,  but  that  they  exert  more 
or  less  of  an  influence  upon  the  respiratory  centre,  producing 
dyspnoea.  Experiments  conducted  in  our  laboratory  by  Dr. 
Underbill  have  shown,  for  example,  that  while  piperidin 
painted  un  the  pancreas  causes  marked  hyperglycemia  and 
consequent  glycosuria,  the  same  result  follows  when  the 
piperidin  is  painted  on  the  spleen,  introduced  intraperi- 
toneally,  or  injected  directly  into  the  blood.  Further,  the 
drug  fails  to  produce  these  results  when  oxygen  is  adminis- 
tered, in  other  words,  as  stated  by  Dr.  Underbill,  ex- 
perimental diabetes  of  this  sort  is  due  simply  to  diminished 
oxidation  of  carbohydrate  material,  with  the  consequent 
accumulation  of  sugar  in  the  blood,  and  elimination  by  the 

•  Underbill:  Certain  Aspects  of  Experimental  Diabetes.  American 
Journal  of  Physiology,  Vol.  id,  p.  xxxvi. 


38  SOME    PROBLEMS    OF 

kidneys.  Dyspnoea  is  always  prone  to  call  forth  marked 
hyperglycemia  and  glycosuria,  whether  induced  by  drugs 
or  otherwise.  Lastly,  may  we  not  query  whether  the  lack  of 
oxidation  of  sugar  and  the  consequent  glycosuria  in  these 
cases  is  not  due  to  conditions  unfavorable  or  inhibitory  to 
the  action  of  the  normal  oxidases  or  other  ferments  which 
ordinarily  are  effective  in  destroying  sugar? 

Another  chapter  in  intermediary  metabolism  well  worthy 
of  consideration  is  that  which  relates  to  the  amino-acids  ; 
but  time  will  not  permit  of  more  than  a  passing  reference  to 
these  interesting  substances,  although  many  of  them  are 
formed  as  products  of  proteid  decomposition  within  the 
body,  and  play  important  parts  in  intermediary  metabo- 
lism. Some  of  them,  however,  are  connected  with  pecu- 
liar anomalies  of  proteid  katabolism,  and  I  may  therefore 
be  pardoned  if  I  refer  to  one  or  two,  since  they  are  associ- 
ated with  conditions  of  the  body  in  which  certain  metabolic 
functions  are  strangely  perturbed.  Cystin  (and  the  related 
body,  cystein)  is  well  known  as  a  primary  crystalline  de- 
composition product  of  proteids  and  is  characterized  by 
containing  the  sulphur  of  the  proteid  molecule  from  which 
it  is  derived.  In  that  somewhat  rare  disease,  known  as 
cystinuria,  cystin  appears  in  the  urine,  sometimes  in  fairly 
large  amounts.  Normally,  the  cystin  which  must  be  split 
off  from  every  sulphur-containing  proteid  during  the  pro- 
cess of  katabolism  is  oxidized  or  destroyed  by  the  processes 
of  intermediary  katabolism  and  disappears.  But  in  cystin- 
uria, the  body  loses  the  power  of  burning  or  oxidizing  this 
substance,  and  hence  it  is  excreted  unchanged.  Now,  it  is 
claimed  that  there  are  two,  isomeric,  forms  of  cystein  ; 
one,  known  as  protein-cystein,  because  of  its  production 
from  horn  and  other  proteids,  and  having  the  formula : 
CH2  .  SH  -  CH  .  NH2  .  COOH,  i.e.,  a-amino-/3-thio- 
propionic  acid ;  while  the  other,  known  as  calculus-cy stein, 
because   obtained   from  urinary  calculi,   has   the  formula  : 


INTERMEDIARY    METABOLISM.  30 

CH2  .  NH2  -  CH  .  SH  -  COOH,  i.  e.,  a-thio-yS-amino- 
propionic  acid.  If  the  so-called  protein-cystein  is  fed  to  a 
person  afflicted  with  cystinuria  the  substance  is  excreted 
unchanged,  simply  increasing  the  amount  contained  in  the 
patient's  urine  ;  but  if  the  isomeric  form,  calculus-cy stein, 
is  fed  it  at  once  disappears,  the  amount  of  sulphate  in  the 
urine  being  correspondingly  increased,  just  as  happens  with 
both  forms  when  introduced  into  the  system  of  the  healthy 
individual.*  In  other  words,  under  the  conditions  prevail- 
in"-  in  cystinuria,  the  body  has  lost  the  power  of  burning 
the  one  form  of  the  amino-acid,  i.  e.,  the  a-amino  acid. 
Indeed,  in  this  condition  of  disease,  intermediary  metabo- 
lism is  so  perverted  that  all  a-inonamino  acids  whenever 
introduced  into  the  system  are  excreted  unchanged,  the 
body  having  apparently  lost  all  power  of  burning  them. 
Thus,  the  a-monamino  acids,  tyrosin,  leucin,  aspartic  acid, 
etc.,  which  are  completely  oxidized  in  the  healthy  organ- 
ism to  carbon  dioxide  and  ammonia,  i.  e.,  as  urea,  are  ex- 
creted almost  quantitatively  when  fed  in  cystinuria.  We 
may  well  pause  here  to  emphasize  the  fine  discrimination 
which  the  body  shows  in  its  treatment  of  these  two  isomeric 
forms  of  cystein  (in  cystinuria).  The  two  substances  are 
essentially  alike,  except  in  the  relative  position  in  the  mole- 
cule of  the  amino  (NH2)  group,  yet  the  one  is  easily  oxi- 
dized, while  the  other  passes  through  the  body  absolutely 
unchanged.  Moreover,  it  is  evident  that  in  cystinuria  this 
inhibition  of  the  power  to  burn  the  a-amino  acid  is  a  gene- 
ral one,  preventing  any  «-amino  acid  from  undergoing 
change  in  the  body. 

Further,  in  cystinuria,  diamino-acids,  such  as  arginin 
and  lysin,  behave  in  a  peculiar  manner.  Unlike  the 
inonamino-acids,  they  undergo  change,  but  it  results  sim- 
ply   in  a  slight  transformation  and  not  in  a  complete  or 

•  Bee  Loewjr  and  Neubetg :  Uebcr  Cystinuric     Zeitschrift  f.  phyniolo- 
giftche  Chemie,  Hand  13,  p.  888. 
5 


40  SOME    PROBLEMS    OF 

profound  oxidation.  Thus,  when  arginin  is  fed  to  a  per- 
son with  cystinuria  it  is  converted  into  the  diamine  putres- 
cine,  viz.,  tetramethylene-diamine  : 

NH2.C(NH)-NH.     CH2  -  (CH2)2-CH.     NH2  -  COOH     ^^ 
Arginin 

NH2  -  CH2  -  (CH2)2  -  CH2  NH2 
Putrescine 

In  a  similar  way  the  diamino-acid  lysin  is  transformed 
into  the  diamine  cadaverine,  vizr,  pentamethylene-diamine  : 

CH2NH2  -  (CH2)3 -CH.     NH2.     COOH     »-»- 
Lysin 

CH2.     NH2  -  (CH2)3 -CH2.     NH2 
Cadaverine 

With  these  facts  before  us  as  illustrations,  it  is  evident 
that  in  such  a  disease  as  cystinuria  many  changes  of  meta- 
bolism may  occur,  by  which  intermediate  products  ordina- 
rily undergoing  progressive  oxidation  are  prevented  from 
suffering  further  change,  and  are  hence  cast  out  of  the 
body  unaltered.  Their  presence  in  undue  quantities,  how- 
ever, is  not  without  possible  physiological  significance. 
For  example,  it  needs  very  little  imagination  to  see  how, 
when  the  body  has  lost  in  greater  or  less  measure  the  power 
to  burn  organic  acids,  a  condition  of  acidosis  may  be  pro- 
duced, and  how  this  condition  may  in  turn  influence  the 
production  of  ammonia  in  the  body  from  the  breaking  down 
of  proteid  in  an  attempt  on  the  part  of  the  latter  to  neu- 
tralize or  overcome  the  influence  of  the  accumulating  acid. 
But  we  have  not  time  to  discuss  this  theme,  however  im- 
portant or  suggestive  it  way  be.  Rather  let  me  bring  to 
your  attention  another  anomaly  of  intermediary  metabolism, 
as  seen  in  alkaptonuria,  a  condition  in  which  the  urine 
shows  the  presence  of  the  peculiar  diphenol  acids  known  as 
homogentisic  and  uroleucic  acids.  It  has  long  been  known 
that  in  this  disease  a  rich  proteid  diet  tends  to  increase  the 


INTERMEDIARY    METABOLISM.  41 

output  of  these  acids,  from  which  the  inference  has  natu- 
rally been  drawn  that  some  cleavage  product  of  the  proteids 
must  be  their  antecedent.  The  presence  of  the  aromatic 
group  suggests  tyrosin  as  one  of  the  antecedents,  and  experi- 
ment has  shown  that  the  ingestion  of  tyrosin  by  persons 
having  alkaptonuria  is  followed  by  an  increased  excretion 
of  homogentisic  acid.  The  same  observation  has  been 
made  with  phenylalanin,  from  which  we  may  conclude 
that  both  of  these  aromatic  substances,  derivatives  of  pro- 
teid  matter,  are  normal  antecedents  of  homogentisic  acid. 
In  other  words,  the  characteristic  acids  found  in  the  urine 
in  alkaptonuria  have  their  origin  in  the  aromatic  complex 
of  the  proteid  molecule  through  the  stage  of  the  two  aro- 
matic substances  mentioned  above.  As  stated  by  Falta,* 
it  is  quite  apparent  that  in  alkaptonuria  there  is  a  profound 
disturbance  in  the  breaking  down  of  the  aromatic  amino- 
acids  which  result  from  proteid  katabolism,  as  a  result  of 
which  uroleucic  or  homogentisic  acid  (or  both)  appear  in 
the  urine.  Under  normal  conditions,  these  two  acids  after 
suffering  deamidization  are  completely  oxidized  to  carbon 
dioxide  and  water.  Thus,  in  the  normal  individual,  homo- 
gentisic acid  introduced  into  the  alimentary  tract  com- 
pletely disappears,  i.  e.,  it  is  entirely  oxidized  to  simpler 
products,  but  when  fed  to  a  person  afflicted  with  alkapto- 
nuria it  appears  quantitatively  in  the  urine.  In  other  words, 
in  alkaptonuria  the  body  has  entirely  lost  the  power  of 
splitting  off  the  benzol  ring  from  the  intermediary  proteid 
product  homogentisic  acid.  On  the  basis  of  experimental 
evidence,  it  is  probable  that  the  progressive  In-caking  down 
of  the  aromatic  amino-acids  derived  from  proteid  katabol- 
ism, after  having  reached  the  tyrosin  or  phenylalanin  stage) 

i-   a-   follows  : 
•   Die  Alk.-ip!    ■  I      itralblatt.  Ban  I  ■'<.  p.  Ml, 


42 


SOME    PROBLEMS    OF 


COOH 
Phcnylalanin 


CH 


(HO)C 
HC 


/\ 

V 


CH 
C(OH) 


c 


CH, 

I 
CHOH 

I 
COOH 

Uroleueic  acicl 


CH2 

I 
CHOH 

I 
COOH 

Phenyl-a-lactic  acicl 
CH 

(HO)C   [        ^|CH 
HC  I  J  C(OH) 


C 
I 
CH2 

I 
COOH 

Homocentisic  acid 


Especially  interesting  and  suggestive  in  this  schematic 
representation  of  the  intermediary  changes  from  phcnylalanin 
to  homogcntisic  acid  is  the  formation  of  phenyl-a-lactic 
acid.  The  splitting  off  of  nitrogen  from  the  alanin,  i.  e., 
its  deamidization,  takes  place  at  this  stage  with  the  resultant 
formation  of  a  non-nitrogenous  acid,  a  complex  of  the  aro- 
matic group  and  rt-lactic  acid.  We  thus  see  opened  up,  as 
stated  by  Falta,  a  new  point  of  view  regarding  the  forma- 
tion of  sugar  from  proteid.  Between  lactic  acid  and  dex- 
trose there  are  many  obvious  physiological  connections  arid 
it  is  quite  conceivable,  to  say  the  least,  that  a  portion  of 
the  lactic  acid  originating  in  this  manner  may  in  the  liver 


INTERMEDIARY    METABOLISM.  43 

be  transformed  into  sugar  or  glycogen.  In  alkaptonuria, 
however,  while  deamidization  of  alanin  may  occur  as  nor- 
mally, oxidation  and  other  changes  stop  at  the  uroleucic  or 
homogentisic  acid  stage,  the  body  cells  having  lost  the 
power  of  splitting  off  or  burning  the  benzol  ring  ;  an  anom- 
aly in  intermediary  metabolism  without  doubt  due  to  the 
absence  or  inhibition  of  the  specific  intra-cellular  enzyme 
which  normally  accomplishes  this  transformation. 

And  so  we  see  on  every  hand  in  studying  the  many  and 
varied  processes  of  intermediary  metabolism,  of  which  the 
foregoing  are  to  be  taken  merely  as  illustrations,  the  sig- 
nificant part  played  by  intra-cellular  enzymes  in  bringing 
about  the  normal  and  abnormal  changes  characteristic  of 
health  and  disease.*  The  processes  which  we  have  hereto- 
fore considered  as  due  to  the  peculiar  vital  properties  of 
the  tissue  cells,  and  which  were  supposed  to  be  entirely 
dependent  upon  their  morphological  and  functional  integrity, 
we  now  see  are  due  —  certainly  in  large  measure,  if  not 
wholly  —  to  a  great  variety  of  enzymes  which  can  be  sep- 
arated from  the  cell  substance  and  which  retain  their  activity 
even  when  free  from  the  influence  of  the  living  protoplasm. 
Further,  we  find  ample  evidence  that  the  varied  processes 
of  katabolism  are  the  result  of  orderly  chemical  changes,  of 
:i  progressive  character,  in  which  cleavage,  hydration,  re- 
duction, oxidation,  deamidization,  etc.,  alternate  with  each 
other  under  the  influence  of  specific  enzymes,  where  chemi- 
cal constitution  and  stereochemical  configuration  of  the  va- 
rious molecules  are  determining  factors  in  the  changes 
produced.  It  is  therefore  evident  that  our  understanding 
of  intermediary  metabolism  will  depend  in  large  measure 
upon  the  intelligent  application  of  the  principles  and  methods 
of  physiological  chemistry  in  our  study  of  these  important 
and  far-reaching  problems. 

,M:     Die  Bedeutung  det  intraceUaULren   Enzyme  in  der 
BiochemUchea  Centralblatt,  Band  ■'>,  p.  886. 


Date  Due 

« 

QP171  C44 

Chittenden 

Some  problems  of  intermediary 
metabolism 

C.  U.  BINDERY 


